Human diseases associated with defects in cell-cell adhesion junctions known as desmosomes have suggested the importance of desmosomal components for the function and maintenance of the skin and ectodermal derivatives, including hair, teeth, nails, and sweat glands. Using knockout mice, we recently identified the Perp tetraspan membrane protein as a component of the p63 stratified epithelial development program, where it plays an essential role in desmosome function and epithelial adhesion in the skin. As a critical desmosomal constituent, Perp inactivation might lead to dysfunction of ectodermal derivatives. To address this hypothesis, we propose to use conditional mice we generated to ablate Perp specifically in the ectoderm and its derivatives and to determine the phenotypes arising in aging adult mice. Through this analysis, we will define the role of Perp in hair follicles, nails, teeth and sweat glands. As the role of desmosomes in ectoderm derivatives is not well understood, our studies will provide new insight into their role in these contexts. Moreover, revealing the consequences of Perp-deficiency in these tissue compartments provides a basis for identifying human diseases associated with Perp-deficiency in the future. To gain insight into the mechanism of Perp action at the desmosome, we will define important functional motifs within Perp by generating a panel of Perp mutants with alterations in specific domains and we will identify Perp-interacting desmosomal proteins. Finally, we propose to examine the role of Perp in the dynamic assembly and disassembly of desmosomes. To determine how Perp promotes desmosomal adhesion, we will establish whether Perp enhances trafficking, clustering or stability of desmosomal proteins at the plasma membrane. To define Perp's role in desmosome dissolution induced by a variety of physiological and pathological stimuli, including growth factors, wounding, and Pemphigus Vulgaris antibodies, we will examine Perp expression, localization and post-translational modification in these settings. These experiments will provide insight into a larger role that Perp may play in desmosome remodeling during such processes as development, wound healing, and cancer. Together, these approaches will provide an understanding of how Perp, desmosomes, and p63 contribute to both epithelial integrity and ectodermal appendage function, and how their dysfunction leads to disease.